WO2011015289A1

WO2011015289A1 - 8-hydroxy-5-[(1r)-1-hydroxy-2-[[(1r)-2-(4-methoxyphenyl)-1-methylethyl] amino]ethyl]-2(1h)-quinolinone hemi-fumarate

Info

Publication number: WO2011015289A1
Application number: PCT/EP2010/004490
Authority: WO
Inventors: Fausto Pivetti; Emilio Lutero
Original assignee: Chiesi Farmaceutici S.P.A.
Priority date: 2009-08-04
Filing date: 2010-07-22
Publication date: 2011-02-10
Also published as: US20110044913A1

Abstract

The invention relates to 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1 R)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]-2(1H)-quinolinone hemi- fumarate salt. The invention also relates to processes for its preparation, pharmaceutical compositions thereof, and to its use as a medicament.

Description

8-HYDROXY-5-[(1 R)-1 -HYDROXY-2-[[(1 R)-2-(4-METHOXYPHENYL)-1 - METHYLETHYL]AMINO]ETHYL]-2(1 H)-QUINOLINONE HEMI-FUMARATE

FIELD OF INVENTION

The present invention relates to a novel 8-hydroxy-5-[(1 R)-1-hydroxy-2- [[(1 R)-2-(4-methoxyphenyl)-1 -methylethyl]-amino]ethyl]-2(1 H)-quinolinone salt.

The invention also relates to pharmaceutical compositions thereof, and to its use as a medicament.

BACKGROUND OF THE INVENTION

The pharmaceutically active compound 8-hydroxy-5-[(1 R)-1-hydroxy-2- [[(1 R)-2-(4-methoxyphenyl)-1 -methylethyl]amino]ethyl]2(1 H)-quinolinone (I), also known as carmoterol, has been described in EP 147719 as a bronchodilator having a potent beta2-adrenoceptor stimulating action

(I)

Two positions in carmoterol structure may be protonated or deprotonated to form salts, i.e. the basic amino group and the phenolic group to form ammonium salts and phenate salts, respectively.

Only carmoterol monohydrochloride salt on the amino group, referred to with the code TA 2005 or CHF 4226, has been widely investigated as a medicament for the treatment of respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

However, the monohydrochloride salt can be obtained in an adequate level of chemical purity and crystallinity only by applying specific crystallization conditions, as reported in WO 2005/089760.

Moreover, said salt is presently under development as formulations for inhalation at very low single doses, ranging from 1 to 4 μg per actuation of the inhaler.

Therefore, in the case of powder or suspension formulations, it is important that the drug disperses well and is uniformly distributed in the composition since a lack of homogeneity, upon administration through the inhaler, could involve a risk of an over- or under-dosage, and hence is detrimental to the possibility of achieving a reproducible accuracy of the delivered dose.

So far, carmoterol monohydrochloride has been found difficult to be dispersed, due to the possible formation of agglomerates which cannot sufficiently be broken by the mixing energy.

Other ammonium salts have generically been disclosed in EP 147719 and in other documents such as WO 2005/013994 and WO 2007/014673, but they have not been further characterized.

In view of the aforementioned problems, it would be advantageous to provide a carmoterol salt which is easy to obtain in a highly crystalline form as well as provided of good handling qualities for pharmaceutical use, in particular in terms of dispersibility in a composition for inhalation.

It has now been found a carmoterol salt meeting said requirements.

SUMMARY OF THE INVENTION

The present invention concerns 8-hydroxy-5-[(1 R)-1-hydroxy-2-[[(1 R)-2- (4-methoxyphenyl)-1 -methylethyl]amino]ethyl]-2(1 H)-quinolinone (carmoterol) hemi-fumarate salt.

The salt of the invention may be produced by crystallization from appropriate solvents and conditions. It is characterized by specific peaks in the X-ray powder diffraction (XRPD) pattern. Accordingly, the invention is also directed to processes for the preparation of said salt by crystallization from appropriate solvents.

In another aspect, the invention provides a pharmaceutical composition comprising the salt of carmoterol, and a pharmaceutically acceptable carrier.

The invention also concerns the salt of the invention for use as a medicament.

In a further aspect, the invention concerns salt of the invention for use for the prevention and/or treatment of an inflammatory or obstructive respiratory disease such as asthma or chronic obstructive pulmonary disease (COPD).

Moreover, the invention concerns the use of the salt of the invention in the manufacture of a medicament for the prevention and/or treatment of an inflammatory or obstructive respiratory disease such as asthma or chronic obstructive pulmonary disease (COPD).

In yet another aspect, the invention provides a method for preventing and/or treating an inflammatory or obstructive respiratory disease such as asthma or chronic obstructive pulmonary disease (COPD)₁ the method comprising administering an effective amount of the salt of the invention to patients in need thereof.

DEFINITIONS

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by the skilled in the art.

The term "hemi-fumarate" refers to the salt of carmoterol with fumaric acid in the 2:1 stoichiometric ratio.

"Fumarate", refers to the salt with a stoichiometrically equimolar amount of fumaric acid.

The term "amorphous" describes a non-ordered solid state characterized by a diffused X-ray powder diffraction with no sharp peaks.

An effective amount of a compound for treating a particular disease is an amount that is sufficient to ameliorate, or in some manner reduce the symptoms associated with the disease.

The term "high level of chemical purity" refers to a compound wherein the total amount of readily detectable impurities as determined by standard methods of analysis, such as high performance liquid chromatography

(HPLC), is less than 5%, advantageously less than 2.5%, preferably less than 1.0, more preferably less than 0.5% w/w.

The term "high level of crystallinity" refers to a polymorph wherein the percentage of crystallinity is equal to or higher than 85% as determined by standard methods of analysis, such as X-ray powder diffraction or microcalorimetry.

The term "good flowability" refers to a formulation that is easy handled during the manufacturing process and is able of ensuring an accurate and reproducible delivering of the therapeutically effective dose.

Flow characteristics can be evaluated by measuring the Carr's index; a Carr's index of less than 25 is usually considered to define good flow characteristics. Otherwise, it can be measured using suitable apparatus such as the Flodex tester.

The term "good homogeneity" refers to a formulation wherein, upon mixing, the content of active material contained in multiple different samples collected throughout the batch is always within 85 and 115%.

The term "respirable fraction" refers to an index of the percentage of active particles which would reach the deep lungs in a patient.

The respirable fraction, also termed fine particle fraction, is evaluated using a suitable in vitro apparata such as Multistage Cascade lmpactor or Multi Stage Liquid lmpinger (MLSI) according to procedures reported in common Pharmacopoeias.

It is calculated by the ratio between the respirable dose and the delivered dose.

The delivered dose is calculated from the cumulative deposition in the apparatus, while the respirable dose (fine particle dose) is calculated from the deposition on Stages 3 (S3) to filter (AF) corresponding to particles < 5.0 micron.

As a thumb rule, a respirable fraction higher than 30% is an index of good inhalatory performances.

"Interactive ordered mixture" refers to a powder wherein the cohesive micronised active ingredient is mixed with free-flowing coarser carrier particles on which surface the micronised particles adhere.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the X-ray diffraction pattern (XRDP) of carmoterol hemi- fumarate.

Figure 2 shows the IR spectrum of carmoterol hemi-fumarate.

Figure 3 shows the Raman spectrum of carmoterol hemi-fumarate. DETAILED DESCRIPTION OF THE INVENTION

It has been found that carmoterol hemi-fumarate salt can be easily and homogeneously dispersed in a carrier for a powder formulation providing a good uniformity of distribution of the active particles, and hence, an adequate accuracy of the metered dose.

Moreover, contrary to the fumarate salt and other salts, the hemi- fumarate salt can be prepared in a highly crystalline form, is readily isolable and exhibits favourable filtration characteristics.

It is also non-hygroscopic and chemically and physically stable in different conditions of humidity and temperature.

Carmoterol hemi-fumarate is preferably anhydrous, but the invention also provides solvates and hydrates of said salt.

In an embodiment of the invention, carmoterol hemi-fumarate has a degree of crystallinity equal to or higher than 85%, advantageously equal to or higher than 90, more advantageously of at least 95%, preferably of at least 98%.

The hemi-fumarate salt may be characterized by analytical methods such as X-ray powder diffraction (XRPD)₁ Infra-Red (IR) and Raman spectroscopy, or by its melting point measured by melting point apparatus or Differential Scanning Calorimetry (DSC).

The hemi-fumarate salt exhibits at least the characteristics XRPD peaks expressed in degrees 2Θ (2-theta) reported in Table 1 :

Table 1

Diffraction Angle (°2Θ)

5.99

11.53

11.96

12.21

14.19

14.32

15.26

18.01

18.29

18.79

19.01

20.61

20.85

21.30

21.95

22.24

23.17

23.44

23.58

24.17

24.42 The term "approximately" means that there is an uncertainty in the measurements of the degrees 2Θ of ± 0.2.

Preferably, the hemi-fumarate salt is characterized by a XRPD pattern comprising characteristic peaks with approximate 2Θ values as indicated in Table 1 , and with relative intensities deviating by no more than ±30%, preferably no more than +10%, from the values given in Table 2.

Table 2

The salt of the invention has an XRPD pattern having characteristic peaks and relative intensities substantially as illustrated in Figure 1.

The salt of the invention may be further characterized by IR spectrum having the main peaks at the following wave numbers (cm-¹) with the relative intensities between brackets:

3415-2135 (broad), 1644 (strong), 1558 (strong), 1353 (strong), 1248 (strong), 872-614 (medium).

It may also be defined as having the IR spectrum having characteristic peaks and relative intensities substantially as illustrated in Figure 2. Raman spectroscopy may also be useful for characterising the salt of the invention having the main peaks at the following wave numbers (cm-¹) with the relative intensities between brackets:

317-2780 (broad), 1650 (medium), 1612 (medium), 1410 (strong), 1330 (very strong).

The salt of the invention has the Raman spectrum having characteristic peaks and relative intensities substantially as illustrated in Figure 3.

The hemi-fumarate salt of carmoterol has a melting range comprised between 191 and 194⁰C as measured by DSC.

The salt of the invention shows a high level of chemical purity and enantiomeric purity.

Advantageously, the chemical purity is higher than 90%, preferably higher 95%, more preferably higher than 98% as determined by High- Pressure Liquid Chromatography (HPLC), while the enantiomeric purity is higher than 95%, preferably higher than 98% as measured by capillary zone electrophoresis.

The solubility of the salt of the invention in different solvents expressed as %, w/v, is reported in Table 3.

Table 3

C⁾ Vertrel XF^® is the trade name for 2,3-dihydodecafluoropentane and is used as a solvent simulating the properties of common HFA propellants like HFA134a as it can easily be handled due to its higher boiling point (55⁰C)

(²⁾ l.o.d.: limit of detection.

The present invention also provides a process for the preparation of the salt of the invention, comprising the following steps:

(i) dissolving carmoterol base in a suitable solvent, optionally under heating;

(ii) dissolving the proper amount of fumaric acid in the minimum possible volume of a suitable solvent;

(iii) adding the solution of the acid to the carmoterol solution;

(iv) cooling and optionally concentrating the obtained solution;

(v) adding a suitable volume of another solvent to promote the crystallization; and

(vi) isolating the precipitate from the solution.

A preferred solvent for both carmoterol base and fumaric acid is ethanol.

A suitable solvent for promoteing the crystallization is isopropyl ether.

The amount of solvents may be adjusted according to the known methods.

The isolation may also be carried out according known, e.g. by filtration.

Carmoterol hemi-fumarate may be formulated in any convenient way.

The invention also provides pharmaceutical compositions comprising the salt of the invention, and one or more pharmaceutically acceptable carriers or excipients such as diluents, wetting agents, emulsifying agents, binders, coatings, fillers, glidants, lubricants, disintegrants, preservatives, stabilizers, surfactants, pH buffering substances, flavouring agents and the like. A comprehensive guidance on pharmaceutical excipients is given in Remington's Pharmaceutical Sciences Handbook, XVII Ed. Mack Pub., N. Y.,

U.S.A.

The salt of the invention may be formulated for oral, buccal, topical, parenteral, vaginal, rectal or inhalation administration, preferably for inhalation administration.

lnhalable compositions include inhalable dry powders, pressurized metered dose inhalers (pMDI) formulations containing propellants such as hydrofluoroalkanes (HFAs) or propellant-free inhalable solution or suspension formulations.

The invention preferably provides a powder formulation for inhalation, comprising the salt of the invention, in the form of interactive ordered mixture wherein the carrier particles have a mass median diameter (MMD) higher than 50 micron, preferably higher than 90 micron.

The carrier particles may comprise one or more pharmacologically inert physiologically acceptable excipients such as crystalline sugars, preferably lactose, most preferably alpha-lactose monohydrate.

More advantageously, said formulation comprises a fraction of coarse particles made of alpha-lactose monohydrate, said particles having a MMD higher than 90 micron, preferably the mass diameter (MD) comprised between 50 micron and 500 micron, more preferably between 150 and

400 micron, even more preferably between 210 and 355 micron.

Preferably, said powder formulation further comprises a fraction of microparticles obtained by co-milling having a MMD lower than 35 micron, and comprising particles of alpha-lactose monohydrate and an additive material selected from anti-adherents such as the amino acids leucine and isoleucine or lubricants such as magnesium stearate; sodium stearyl fumarate stearyl alcohol, stearic acid and sucrose monopalmitate.

More preferably, said powder formulation comprises a fraction of microparticles having a MMD lower than 15 micron, preferably lower than 10 micron, comprising particles of alpha-lactose monohydrate and particles of magnesium stearate.

Due to its dispersibility and solubility characteristics, the salt of the invention may also turn out to be particularly suitable for providing pMDI formulations wherein the active ingredient is in suspension since carmoterol hemi-fumarate is practically insoluble in HFA propellants.

The salt of the invention in the aforementioned powder and pMDI formulations is advantageously used in micronised form.

Advantageously, at least 90% of the micronised particles have a volume diameter lower than 10 micron, more advantageously equal to or lower than 8 micron.

Preferably the micronised particles have a particle size distribution wherein: i) no more than 10% of the particles have a volume diameter [d(v,0.1)] lower than 0.7 micron, preferably lower than 0.8 micron ii) no more than 50% of particles have a volume diameter [d(v,0.5)] lower than 1.7 micron, preferably comprised between 2 and 4 micron; and iii) at least 90% of the particles have a volume diameter equal to or lower than 8 micron, preferably lower than 6 micron.

The dosage of the salt of the invention can vary within wide limits depending on the nature of the disease to be treated, the type of patient and the mode of administration and will be determined according to known methods.

Upon inhalation, a typical daily dosage is within the range of 1 μg to 8 μg, preferably of 2 to 4 μg administered once or twice a day.

The salt of the invention may be used in combination with one or more other therapeutic agents, preferably those currently used in the treatment of respiratory disorders, e.g. corticosteroids such as budesonide and its epimers, beclometasone dipropionate, triamcinolone acetonide, fluticasone propionate, flunisolide, mometasone furoate, rofleponide and ciclesonide, anticholinergic or antimuscarinic agents such as ipratropium bromide, oxytropium bromide, tiotropium bromide, glycopyrrolate bromide and phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast. The combination with budesonide is preferred.

Carmoterol hemi-fumarate may be used for the preparation of a medicament for any disease or condition in which it is therapeutically effective.

In view of its beta2-adrenoceptor stimulating activity, the salt of the invention is useful in the relaxation of bronchial smooth muscle and the relief of bronchoconstriction. Relief of bronchoconstriction can be measured in models such as the in vivo guinea pigs model (see Kikkawa et al Biol Pharm Bull 1994, 17(8), 1047-1052) and analogous models.

Therefore, administration of the salt of the invention may be indicated for the prevention and/or treatment of mild, moderate or severe acute or chronic symptoms or for prophylactic treatment of obstructive respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Other respiratory disorders characterized by obstruction of the peripheral airways as a result of inflammation and presence of mucus such as chronic obstructive bronchiolitis and chronic bronchitis may also benefit from their use.

The invention is further illustrated by the following examples.

EXAMPLES

Example 1 - Preparation of carmoterol hemi-fumarate

In a 1 I flask carmoterol free base (20 g, 0.054 mol) is dissolved in 400 ml of refluxing ethanol 95% v/v.

Fumaric acid (3.16 g, 0.027 mol) is dissolved in hot ethanol and added to the solution. The mixture is concentrated under vacuum until approximately 200 ml of ethanol are distilled off, then 100 ml of diisopropyl ether is slowly added to the solution at 40-50⁰C. After cooling, the salt in form of a solid crystallizes; it is filtered, triturated in 100 ml of ethyl ether, filtered again and dried at 40⁰C under vacuum for 15 hours. The crude product (17 g) is dissolved in 425 ml of refluxing ethanol, the solution is cooled to 1O⁰C, stirred at 10⁰C for 60 minutes, then the crystallized solid is filtered, and washed with 20 ml of ethanol.

Yield: 13.5 g (58.3%);

Assay (HPLC): > 99.5%;

Enantiomeric purity (CZE): 100%

Melting range (DSC): 191-194⁰C

Example 2 - Solid state characterization

The hemi-fumarate salt, obtained as a white powder, is analyzed for solid state, e.g. by XRPD, IR and Raman spectroscopy

1. X-ray powder diffraction (XRPD)

The XRPD analysis is carried out on a Thermo Electron X-ray powder diffractometer using Cu Ka radiation. A theta-two theta continuous scan from 5 degrees 2 theta to 35 degrees 2 theta is used. The sample is prepared for analysis by placing it in a quartz sample holder.

The XPRD pattern is shown in Figure 1.

2. IR spectrum

The IR spectrum is acquired on a Perkin-Elmer FT-IR spectrophotometer Spectrum 400 (scan range 4000-400 cm-¹).

It is reported in Figure 2.

3. Raman spectrum

The Raman spectrum is obtained with a Perkin-Elmer. FT-Raman spectrometer System 2000R supplied with radiation of 1064 nm and a

InGaAs detector (scan range 4000-200 cm^'1).

It is reported in Figure 3.

Example 3 - Preparation of micronised carmoterol hemi-fumarate.

A batch of formoterol fumarate dihydrate is milled in a nitrogen fluid jet mill apparatus MC 50 (JET Pharma S.A). The particle size distribution and other physico-chemical characteristics are reported in Table 4.

Table 4

Carmoterol hemi-fumarate

Particle size (μm)

- d (v, 0.1 ) 0.79

- d (V, 0.5) 3.73

- d (v, 0.9) 7.58

Assay (HPLC) > 99.5%

PXRD crystalline

As it can be appreciated from Table 3, upon milling, the salt of the invention remains crystalline and its chemical purity is not altered. The batch is then added to a carrier made of coarser particles.

The homogeneous dispersion of the active ingredient in the powder, and the absence of aggregates of active particles is established using a Near Infrared spectrophotometer equipped with a microscopy imaging system (Near Imaging).

The salt of the invention in micronised form uniformly disperses into the carrier and after 180 minute of mixing s no agglomerates are observed.

Example 4 - Exemplary inhalable dry powder formulation comprising carmoterol hemi-fumarate

The formulation is prepared according to the teaching of WO 01/78693. The composition is reported in Table 5. Table 5

Example 5 - Characterisation of the formulation of Example 4

The technological characteristics and aerosol performances of the formulation of Example 4 are evaluated after loading in a multidose dry powder inhaler.

The uniformity of distribution of the active ingredient is evaluated by taking 10 samples, each equivalent to about from one to three doses, from different parts of the blend.

The flowability is evaluated from the Carr's index by determining the poured density (dv) and the tapped density (ds) as follows. Powder mixtures (20 g) are poured into a glass graduated cylinder and dv was calculated dividing the weight by the volume; ds is calculated from the volume obtained after tapping the powder mixture 500 times using a commercially available apparatus.

The flowability is evaluated from the Carr's index calculated according to the following formula: Carr's index (%) = (ds - dv)/ds x 100

The flowability properties are also determined by using a Flodex tester according to the method reported in the European Pharmacopeia 4^th Ed, 2002, paragraph 2.9.16.

The powder mixture is poured into a dry funnel equipped with an orifice of suitable diameter that is blocked by suitable mean. The bottom opening of the funnel is unblocked and the time needed for the entire sample to flow out of the funnel recorded.

The flowability is expressed in seconds related to 100 g of sample (s/100 g).

The emptying index is defined as the percentage of the powder flown through a metered diameter hole to the tested amount of the sample.

The evaluation of the aerosol performance is carried out using the Multi Stage Liquid lmpinger (MSLI) apparatus (Apparatus C) according to the conditions reported in the Eur Ph 4^th Ed 2002, par 2.9.18, pages 213-219. After aerosolization of 10 doses, the MSLI apparatus is disassembled and the amounts of drug deposited in the stages are recovered by washing with a solvent mixture and then quantified by HPLC. The following parameters are calculated: i) the delivered dose which is the amount of drug delivered from the device recovered in the impactor; H) the fine particle dose (FPD) which is the amount of delivered dose recovered below 5.0 micron; Hi) the fine particle fraction (FPF) which is the percentage of the fine particle dose relative to the delivered dose reaching the stage 2 of TSI.

The results are reported in Table 6. Table 6 - Technological characteristics and aerosol performances

Poured density (g/ml)) 0.65

Tapped density (g/ml) 0.74 Carr's index (%) 12.2

Flow rate through 4 mm 0 (s/100 g) 138

Emptying index (%) 98.5

Uniformity of distribution of the active ingredient (%) 105

Delivered dose (μg) 1.05 FPD (μg) 0.53

FPF (%) 50.1

The powder formulation comprising the salt of the invention shows a good uniformity of distribution of the active ingredient with an average content uniformity of 105% and no sample with a value outside the limits 85 and 115%.

The flowability is also very good as demonstrated by the low Carr's index and by the emptying index near to 100%.

Moreover, the aerosol performances of the formulation are very good with about than 50% of respirable fraction.

Claims

1. Crystalline 8-hydroxy-5-[(1 R)-1 -hydroxy-2-[[(1 R)-2-(4-methoxyphenyl)- 1-methylethyl]amino]ethyl]-2(1 H)-quinolinone hemi-fumarate salt.

2. The salt according to claim 1 having a X-ray powder diffraction pattern comprising characteristic peaks expressed in angle 2-theta at approximately: 5.99; 11.53; 11.96; 14.19; 14.32; 15.26; 18.01 ; 18.29; 18.79; 19.01 ; 20.61 ; 20.85; 21.30; 21.95; 22.24; 23.17; 23.44; 23.58; 24.17; 24.42; 26.93.

3. A process for preparing the salt of claim 1 comprising the step of:

(i) dissolving carmoterol base in a suitable solvent, optionally under heating;

(ii) dissolving the proper amount of the fumaric acid in the minimum possible volume of a suitable solvent;

(iii) adding the solution of the acid to the carmoterol solution;

(iv) cooling and optionally concentrating, the obtained solution;

(vi) isolating the precipitate from the solution.

4. A pharmaceutical composition comprising the salt according to claim 1 in admixture with a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4 further comprising a therapeutic agent selected from corticosteroids, anticholinergic or antimuscarinic agents and phosphodiesterase-4 (PDE-4) inhibitors.

6. The pharmaceutical composition according to claim 5, wherein the corticosteroid is budesonide.

7. The pharmaceutical composition according to any one of claims 4 to 6 in the form of an inhalable aerosol comprising a propellant.

8. The pharmaceutical composition according to any one of claims 4 to 6 in the form of an inhalable dry powder.

9. The salt of claim 1 for use as a medicament.

10. The salt of claim 1 for use for the prevention and/or treatment of an inflammatory or obstructive respiratory disease.

11. The salt according to claim 10, wherein the respiratory disease is asthma or chronic obstructive pulmonary disease (COPD).